Delineation of the GPR15 receptor-mediated Gα protein signalling profile in recombinant mammalian cells

Basic Clin Pharmacol Toxicol. 2022 Aug;131(2):104-113. doi: 10.1111/bcpt.13738. Epub 2022 Jun 1.


The GPR15 receptor is a G protein-coupled receptor (GPCR), which is activated by an endogenous peptide GPR15L(25-81) and a C-terminal peptide fragment GPR15L(71-81). GPR15 signals through the Gi/o pathway to decrease intracellular cyclic adenosine 3',5'-monophosphate (cAMP). However, the activation profiles of the GPR15 receptor within Gi/o subtypes have not been examined. Moreover, whether the receptor can also couple to Gs , Gq/11 and G12/13 is unclear. Here, GPR15L(25-81) and GPR15L(71-81) are used as pharmacological tool compounds to delineate the GPR15 receptor-mediated Gα protein signalling using a G protein activation assay and second messenger assay conducted on living cells. The results show that the GPR15 receptor preferentially couples to Gi/o rather than other pathways in both assays. Within the Gi/o family, the GPR15 receptor activates all the subtypes (Gi1 , Gi2 , Gi3 , GoA , GoB and Gz ). The Emax and activation rates of Gi1, Gi2 , Gi3, GoA and GoB are similar, whilst the Emax of Gz is smaller and the activation rate is significantly slower. The potencies of both peptides toward each Gi/o subtype have been determined. Furthermore, the GPR15 receptor signals through Gi/o to inhibit cAMP accumulation, which could be blocked by the application of the Gi/o inhibitor pertussis toxin.

Keywords: BRET; GPR15; Gα protein; second messenger; signalling.

MeSH terms

  • Animals
  • GTP-Binding Proteins* / metabolism
  • Mammals / metabolism
  • Pertussis Toxin / metabolism
  • Pertussis Toxin / pharmacology
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction*


  • Receptors, G-Protein-Coupled
  • Pertussis Toxin
  • GTP-Binding Proteins